Patent GB-773780-A (GB)
Title: Improvements in or relating to the preparation of substituted morpholines
IPC: C07D/
Filed: 1953-07-01
Abstract: The invention comprises compounds of the general formula <FORM:0773780/IV(b)/1> where R1 is an unsubstituted phenyl radical and R2 is an alkyl group having from 1 to 5 carbon atoms or R1 is a mono-hydroxy-phenyl radical and R2 represents a hydrogen atom.  It also comprises a process for the preparation of substituted morpholines of the formula <FORM:0773780/IV(b)/2> where R1 is a phenyl residue which may be substituted by a hydroxyl group or an alkyl or alkoxy residue having from 1 to 5 carbon atoms, R2 and R3 are hydrogen atoms or alkyl or phenyl residues and R4 is a hydrogen atom or a phenyl residue, in which substituted diethanolamines of the general formula <FORM:0773780/IV(b)/3> are treated with acid.  The ring closure can be effected by treatment of the substituted diethanolamine (as the free base or as a salt) with concentrated sulphuric acid at room temperature or with dilute aqueous or alcoholic acid, such as sulphuric, hydrobromic or hydrochloric acid, at below 100 DEG  C.  The substituted diethanolamines can be prepared by reacting benzylethanolamine with a halogenated ketone and subjecting the aminoketone obtained to catalytic hydrogenation to split off the benzyl group and to reduce the keto group to a carbinol group.  In Example (1) b  - phenyl - b ,b 1 - dihydroxy-diethylamine hydrochloride is allowed to stand in concentrated sulphuric acid, giving 2-phenyl-morpholine.  Similarly obtained are (2) 2 - phenyl - 3 - methyl - morpholine; (3) 2,3-diphenylmorpholine; (4) 2,6-diphenylmorpholine.  In further examples: (5) 2-phenyl-3-ethylmorpholine is prepared by treatment with sulphuric acid of 1-phenyl-1-hydroxy-2-ethanolaminobutane (obtained by hydrogenation of the aminoketone produced by reacting 1-phenyl-1-keto-2-bromo-butane with benzylethanolamine) and converted to its bioxalate; (6) benzylethanolamine is reacted with the bromination product of p-methyl-acetophenone, the 1-(p-tolyl) - 1 - keto - 2 - benzyl - ethanolamine obtained is hydrogenated to give 1-(p-tolyl)-1-hydroxy-2-ethanolaminoethane, treatment of which with 30 per cent sulphuric acid on the water-bath gives 2 - (p - tolyl) - morpholine; (7) 2 - phenyl - 1 - hydroxy - 1 - (p - methoxyphenyl) - 2 - ethanolamino - ethane hydrochloride (produced by hydrogenation of 2-phenyl - 1 - keto - 1 - (p - methoxyphenyl) - 2 - benzylethanolamine hydrochloride, obtained by reacting 2 - phenyl - 1 - keto - 1 - (p - methoxyphenyl) - 2 - bromoethane with benzylethanolamine) is boiled with 5 per cent hydrochloric acid to give 3-phenyl-2-(p-methoxyphenyl) morpholine; (8) 1-(p-hydroxyphenyl)-1-keto-2-ethanolamine hydrochloride (from 1-(p-hydroxyphenyl) - 1 - keto - 2 - bromoethane and monoethanolamine) is hydrogenated in methanol in presence of palladium.  After distillation of methanol, 2 - (p - hydroxyphenyl) - morpholine hydrochloride is obtained; (9) b -phenyl-b ,b 1-dihydroxydiethylamine hydrochloride (from the hydrogenation of the reaction product of bromopropiophenone and benzylethanolamine) is heated with 10 per cent hydrochloric acid to give 2-phenyl-3-methyl-morpholine; (10) b ,b 1-diphenyl - b ,b 1 - dihydroxy - a ,a 1 - dimethyldiethylamine (from the reduction of the N-benzyl - b ,b 1 - diphenyl - b ,b 1 - diketo - a ,a 1 - dimethyl-diethylamine obtained on reacting 1 mol. of benzylamine with 2 mols. of 1-phenyl-1-keto-2-bromopropane) treated with concentrated sulphuric acid gives 2,6-diphenyl-3,5-dimethylmorpholine; (11) 1 - (3 - hydroxyphenyl) - 1 - hydroxy - 2 - ethanolaminoethane (obtained by the catalytic reduction of 1-(3-hydroxyphenyl)-1-keto-2-ethanolamine) is heated with 20 per cent hydrochloric acid to give 2-(m-hydroxyphenyl) - morpholine.  Specification 662,829 is referred to.  Reference has been directed by the Comptroller to Specification 705,543.